In preliminary brain magnetic resonance imaging (MRI) studies of children, we have noted decreased frontal lobe volumes. Based on these results, we hypothesized that early onset depression is associated with a decreased frontal lobe volume. While similar findings have been reported in adult populations with major depression, little is known about brain changes in children or adolescents with mood disorders. This is an R01 application for three years of funding to use a multidisciplinary approach to recruit and evaluate 100 adolescents with major depression and 100 comparison subjects. Concurrent measures of (1) frontal lobe and whole brain volumes will be derived from a morphometric analysis of magnetic resonance images (MRI); 2) orbitofrontal N-acetyl-L-aspartate and cytosolic, choline containing compound levels will be assessed using proton magnetic resonance spectroscopy (1H MRS); (3) cognitive functioning will be evaluated using a battery of neuropsychological tests designed to evaluate the functional integrity of the frontal lobes, as well as general intellectual ability; and (4) obstetrical complications will be assessed and scored so their association to the first 3 measures can be examined. One hundred adolescents meeting DSM-IV criteria for major depressive disorder will be recruited from the Department of Psychiatry and the Division of Adolescent/Young Adult Medicine of an urban teaching hospital and consecutively referred for brain imaging and neuropsychological testing. One hundred adolescent comparison subjects will be recruited from the Division of Adolescent/Young Adult Medicine and by newspaper advertisement. These subjects will be free of medical, neurological, and psychiatric disorders. The feasibility of recruiting adolescent comparison subjects who are willing to complete this research protocol has already been tested in a pilot study funded by a private foundation. Data from the 50 comparison subjects who have completed the pilot study will be available for analysis in the research proposed in this application.